Future comparative effectiveness studies:
unanswered questions
in the care of IBD patients
Jean-Frédéric Colombel
Icahn School of Medicine at Mount Sinai
New York, USA
Disclosure
J-F Colombel has served as consultant, advisory board member or speaker for or
received research grants from
Abbvie, Amgen, Bristol Meyers Squibb, Celltrion, Ferring, Genentech, Giuliani SPA,
Given Imaging, Janssend and Janssen, Merck & Co., Millenium Pharmaceuticals Inc.,
Nutrition Science Partners Ltd., Pfizer Inc. Prometheus Laboratories, Sanofi,
Schering Plough Corporation, Takeda, Teva Pharmaceuticals, UCB Pharma, Vertex,
Dr. August Wolff GmbH & Co.
What is comparative effectiveness research (CER) ?
• The generation and synthesis of evidence that compares the benefits and
harms of alternative methods to prevent, diagnose, treat, and monitor
a clinical condition, or to improve the delivery of care.
• The purpose of CER is to ‘‘assist consumers, clinicians, purchasers,
and policy makers to make informed decisions that will improve health
care at both the individual and population levels.’’
• Two key elements are
1) the direct comparison of effective interventions
2) The application of these interventions in patients who are typical
of day-to-day clinical practice
Ratner R , et al. In: Medicine Io.ed Washington DC 2009; Sox HC, et al. Ann Interm Med 2009.
Why do we need CER in IBD ?
Clinical trials
Clinical practice
• Defined population
• Heterogeneous population
• Prescribed treatment regimen
• Variable treatment regimen with
• Follow-up regimented with schedule
• Uniform primary end-point
• Efficacy
optimization
• Follow-up not fixed
• Variable outcomes
• Effectiveness
Clinical trial IBD population versus real-world
IBD population
Retrospective study of patients with moderate-severe IBD at a
US tertiary referral centre (n=206)
31% of patients were not eligible for participation
in a clinical trial of biologic therapy*
Reasons for exclusion in CD
● Strictures or abscesses (62%)
● Recent exposure or
nonresponse to anti-TNF (51%)
● High-dose steroids (18%)
● Comorbidities (26%)
Reasons for exclusion in UC
● Current rectal therapy use (57%)
● Steroid and immunomodulator
naive (45%)
● Newly diagnosed (17%)
● Colectomy likely (15%)
Non-eligible CD patients had a significantly lower response rate to biologics than
eligible CD patients (60% vs 89%, p=0.03)
*Inclusion criteria based on those published for 9 trials of biologic therapy: ACCENT I, CLASSIC I, CHARM, PRECISE I, ENCORE, ENACT, SONIC, ACT 1, ACT 2
Ha C, et al. Clin Gastroenterol Hepatol 2012.
The impact of CE studies: SONIC:
Corticosteroid-Free Clinical Remission at Week 50
Patients with CRP 0.8 mg/dL and Lesions
on Baseline Endoscopy*
100
P=.002
Percent of patients (%)
80
P=.016
P=.354
60
50.0
41.5
40
22.7
20
17/75
27/65
32/64
0
AZA+ placebo
IFX + placebo
IFX + AZA
* Patients who did not enter the study extension were treated as nonresponders
AZA=azathioprine; IFX=infliximab
Colombel JF, et al. N Engl J Med. 2010
Setting priorities for CER in IBD: results of an
international provider survey, expert rand panel, and
patient focus groups
Cheifetz AS , et al. Inflam Bowel Dis 2012.
Unanswered questions…
Flying
Take-off
Landing
Unanswered questions…
Take-off
Which biologic ?
Comparing biologics agents in IBD
The anti-TNFs family
IFX
ADA
CZ
Outcomes in CD patients receiving adalimumab
or infliximab therapy
Retrospective cohort of US Medicare data (2006–2010) from new users of
adalimumab (n=871) and infliximab (n=1,459)
Primary outcomes at Week 26
Adalimumab
Infliximab
Persistence (%)
47
49
OR 0.98, 95% CI 0.81-1.19
Surgery
6.9
5.5
HR 0.79, 95% CI 0.60-1.05
Hospitalisations
15.4
11.8
HR 0.88, 95% CI 0.72-1.07
Primary outcomes according to baseline steroid exposure
Adalimumab
Infliximab
Steroids
7.2
5.6
HR 0.77, 95% CI 0.51-1.14
No steroids
6.5
5.3
HR 0.82, 95% CI 0.55-1.23
Steroids
17.3
13.1
HR 0.86, 95% CI 0.65-1.12
No steroids
13.5
10.7
HR 0.90, 95% CI 0.67-1.20
Surgery
Hospitalisations
Osterman M, et al. Clin Gastroenterol Hepatol 2013
Vedolizumab in UC: Clinical Response, Clinical Remission,
Mucosal Healing at 6 Weeks, ITT Population
50
47.1
Placebo
45
P<0.0001
Vedolizumab
40
P=0.0010
40.9
35
30
25.5
% 25
24.8
P=0.0010
16.9
20
15
10
5.4
5
0
Clinical Response
Clinical Remission
Mucosal Healing
 21.7
11.6, 31.7
 11.5
4.7, 18.3
 16.1
6.4, 25.9
95% CI:
Feagan B et al New Engl J Med 2013
Comparing biologics agents in IBD
AntiTNFs
IFX
ADA
AntiIntegrins
CZ
“The key research topic in the area of IBD from
the US Institute of Medicine (IOM) report is
to compare the effectiveness of competing
biologic agents”
Biologic vs surgery ?
The LIRIC -trial
Combo vs mono ?
Steroid-free Remission at Week 26
Primary End Point
100
Proportion of Patients (%)
P<0.001
80
P=0.009
P=0.022
57
60
44
40
31
20
0
52/170
AZA + Placebo
Steroid-free remission=CDAI <150 points
Colombel JF et al. N Engl J Med 2010
75/169
IFX + Placebo
96/169
IFX+ AZA
SONIC
Impact of concomitant immunomodulator treatment on efficacy
and safety of anti-TNF therapy in Crohn’s disease: a metaanalysis of placebo-controlled trials using patient-level data
Results: 6 Month Clinical Remission Stratified by anti-TNF agent
Adalimumab
Certolizumab
Infliximab
OR 0.88 (0.58-1.35)
OR 0.93; (0.65-1.34)
OR 1.79 (1.06-3.01)
Jones J et al. DDW 2013
Methotrexate with IFX vs IFX alone in CD
COMMIT
Steroid-free remission
% success
Primary end-point:
Failure to enter
steroid-free
remission at week
14 or maintain
through week 50
80
70
60
50
P = 0.83
76.2
77.8
P = 0.86
55.6
40
30
20
10
0
Week 14
MTX
Week 14
57.1
Week 50
MTX
- Highest success rate ever observed
- At week 14 and 50 there was
between the IFX group vs IFX+MTX
group
- All patients on prednisone 15 to
40mg/d
Placebo
Placebo
Week 50
Feagan B et al. Gastroenterology in press
Step-up vs
Accelerated step-up vs
Top-down ?
Conventional and evolving treatment strategies in CD
Ordás I et al. Gut 2011
Early “top-down” therapy with azathioprine is not more
effective than placebo or conventional therapy
RAPID
Cosnes J et al. Gastroenterology 2013;145: 758-65
AZTEC
Panes J et al. Gastroenterology 2013;145: 766-74
Early top-down biologic therapy vs conventional
management of Crohn’s disease
Patients (%)
CDAI <150 AND no steroids AND no surgery
**
*
*
Weeks
*p<0.01
**p<0.05
D’Haens G, et al. Lancet 2008;371:660-7.
Usual care vs accelerated care : REACT 1
20 practices
(1,200 pts)
20 practices
(1,200 pts)
60 patients
per practice
Accelerated care
treatment
algorithm
Usual care
Primary endpoint: Proportion in remission (HBI 4 and off steroids) at practice level 12 mo following randomization
Patients will be bio-naïve
Accelerated care therapeutic algorithm for Crohn’s disease
Active luminal CD (HBI >4)
5-ASA
Antibiotics
Without fistula
With fistula
Steroids (budes vs pred based on
disease activity and location)
Evaluate in 4 wks – remission? (HBI ≤4)
No
Yes
Taper steroids
Re-evaluate in 12 wks – remission?
Yes
No maintenance
therapy
Add ADA + AZA or MTX
Yes
MRI, US, EUA
to rule out abscess
No
Taper steroids, re-evaluate
in 12 wks – remission?
Yes
Yes
Switch anti-metabolite
Re-evaluate in 12 wks – remission?
No
Yes
Cont combo maint Rx
No
Re-evaluate in 4 wks
– improved?
No
No
Re-evaluate in 12 wks – remission?
No
Cont combo maint Rx
Antibiotics/
fistulotomy
Drainage/seton
+ antibiotics
Increase ADA to weekly dose
Yes
No
Abscess
present?
ADA + AZA or MTX
(steroids prn)
Re-evaluate in 12 wks – remission?
Yes
Cont combo maint Rx
Complex fistula
Surgical
reassessment
Follow algorithm for active
luminal CD without fistula
Switch TNF-blocker
Yes
Cont combo maint Rx
Re-evaluate in 12 wks – remission?
No
Consider resection
Unanswered questions…
Flying
Treat to mucosal healing vs
treat to symptoms ?
Usual care vs enhanced care : REACT 2
15 practices
(600 pts)
15 practices
(600 pts)
40 patients
per practice
Enhanced care
treatment
algorithm
Step care
treatment
algorithm
Primary endpt: risk of CD-related complications at one-year, measured at the practice level. CD-related complications
include (1) CD-related hospitalizations for CD-related surgeries and non-surgical CD events (such as disease flare, bowel
obstruction, excluding hospitalization for side effects of study medication), and
(2) Bowel damage events not requiring hospitalization (such as symptomatic bowel obstruction, cutaneous fistula,
abscess).
Enhanced care algorithm
5-ASA
Antibiotics
Active luminal CD (HBI >4, 1 large ulcer)
Initiate combination therapy (adalimumab + AZA or MTX) +/- GCS as required
Evaluate by ileocolonoscopy in 16 wks – remission?
(HBI ≤4, no large ulcers, no GCS)
Yes
No
Continue combination
maintenance therapy
Increase adalimumab to weekly dose +/- GCS as required
Taper GCS, re-evaluate by ileocolonoscopy in 16 wks
– remission? (HBI ≤4, no large ulcers, no GCS)
Yes
No
Continue combination
maintenance therapy
Switch antimetabolite, +/- GCS as required
Yes
Continue combination
maintenance therapy
Re-evaluate by ileocolonoscopy in 16 wks
– remission? (HBI ≤4, no large ulcers, no GCS)
No
Switch TNF antagonist, +/- GCS as required
Treat to biomarkers vs
treat to symptoms ?
Calprotectin monitoring in CD after IFX
withdrawal
Usual care vs tight control using biomarkers: CALM
Open-label, multicenter study in Europe and Canada
Evaluating two treatment algorithms in CD
Conventional
CDAI, steroid use
Patients naïve to
immunomodulators
and biologic therapy
(n=240)
Prednisone
up to 8 weeks
Primary endpoint:
Mucosal healing 48 weeks
after randomisation
Tight control
CDAI, steroid use, high-sensitivity CRP, faecal calprotectin
Treatment intensification in both arms:
1) No treatment, 2) Adalimumab every other week,
3) Adalimumab weekly, 4) Adalimumab weekly + azathioprine
www.clinicaltrial.gov: NCT01235689
Tight control arm
Y = No change**
Y = No change**
N = ADA EOW**
N = ADA EOW**
Y = No change**
N = ADA wkly
Y = No change**
N = 120
Prednisone
8 wks
N = ADA
Y = No change** N = ADA wkly
N = ADA wkly**
Y = ADA EOW**
w9
w21
w33
Y = No change**
N = ADA wkly**
Y = No change**
N = ADA wkly**
Y = ADA EOW**
N = ADA wkly AZA**
Y = No change**
N = ADA wkly**
At week 9, 21, 33 and 45,
did subject meet all
objective criteria?:
– CDAI <150
– HS-CRP <5mg/L
– Calprotectin <250 μg/g
– Off steroids starting
wk 9
Y = ADA EOW**
N = ADA wkly AZA**
Y = No change**
N = ADA wkly**
Flare = CDAI↑ ≥70 from BL and
≥220, pt continues as nonresponder
Y = ADA EOW AZA** * Flare between wks 9 + 21, ADA
N = ADA wkly AZA** started
N = ADA
wkly + AZA
R
Y = No change**
N = ADA EOW**
Treatment may change at
weeks 9, 21, 33 and 45
based on success criteria
at weeks 8, 20, 32 and 44
w45
w56
** Flare between evaluation wks,
then next option
Treat to trough levels vs
treat to symptoms ?
Pk of biologics: What we know already
• Drug levels of IFX and ADA are associated with outcome in
Crohn’s disease
• Antibody status is not directly associated with outcome but
is important in understanding reasons for loss of response
(LOR) to anti-TNF
• Dose escalation can increase drug levels
• Immunomodulation can decrease antibody production
Colombel JF, et al. Inflamm Bowel Dis 2012
Date of preparation September
Individualised therapy vs dose intensification in patients
with CD who lose response to anti-TNF
Randomised, single-blind, multicentre Danish study in CD (n=69)
Patients with secondary IFX failure were randomised to IFX dose intensification
(5 mg/kg every 4 weeks) or interventions based on serum IFX and IFX antibody levels
Intention-to-treat
Per protocol
-50%
-25%
0%
25%
50%
True difference
IFX intensification
better
Algorithm
better
Cost per patient, € mean
10
8
*p<0.001
*
IFX
intensification
6
*
4
Algorithm
2
0
0
4
8
12
Study week
Co-primary clinical endpoint in intention-to-treat and per protocol
populations. Dashed lines illustrate the predefined non-inferiority margin
Steenholdt C , et al. Gut 2013; gutjnl-2013-305279 [ePub ahead of print]
Co-primary economic endpoint in per protocol populations.
Data are average treatment per patient
Optimizing anti-TNF based on trough levels vs clinical symptoms:
TAILORIX
Biologic Naïve Subjects with active luminal CD (N=120)
Ileocolonoscopy
at screening
Visits
Week 0 *
Week 2 *
Week 6 *
Week 12
Cohort 1
n=40
Cohort 2
n=40
Cohort 3 (control)
n=40
IFX 5 mg/kg (0,2,6 then every 8 wks)
+ AZA 2-2.5 mg/kg (if tolerated)
Ileocolonoscopy/TL
Week 14
18
Week 22
26
Week 30
34
Week 38
42
Week 46
50
*
*
*
Upon Clinical Relapse
†
and/or TL ↓:
-1st time: IFX 7.5 mg/kg
-2nd time: IFX 10mg/kg
Upon Clinical Relapse
†
and/or TL ↓:
-IFX 10 mg/kg
Only upon
Elevated CDAI:
-IFX 10 mg/kg
*
*
Week 54 *
Ileocolonoscopy
Primary endpoint: steroid-free remission between wk22 and wk54
(CDAI < 150) and endoscopic healing at wk54
Unanswered questions…
Landing
Discontinuation of Immunomodulator in Stable Remission
on Combination Therapy (Infliximab Maintained)
No need for early ‘rescue’ IFX:
primary endpoint
1.0
Median IFX levels,
Week 8 to Week 104 combined
100
0.8
Log Rank (Cox): 0.735;
Breslow: 0.906
0.6
IFX trough levels
(μg)
Cumulative survival
p<0.005
10
0.4
Continued
Discontinued
0.2
1
0.0
0
0
20
40
60
80
100
Continued
Discontinued
Time (weeks)
 80 patients randomized to continue (+CON , n=40) or to interrupt (++DIS, n=40) immunomodulators
(azathioprine or methotrexate) 6 months after the start of infliximab (5 mg/kg IV)
Van Asche et al, Gastroenterology 2008
Discontinuation of Infliximab in Stable Remission on
Combination Therapy (azathioprine maintained)
STORI
• n=52 relapses/115 patients
• Median follow-up 28+/- 2 months
• Median time to relapse: 16.4 months
Louis E et al. Gastroenterology. 2012;142:63-70.
Predictive Model for Time to Relapse After
Stopping IFX and Continuing AZA
Kaplan Meier time-to-relapse curves according to multivariate models and
scores generated through Cox model using multiple imputations method
Deleterious factors:
• No previous surgery
• Steroids within 12-6 months
before infliximab withdrawal
• Male gender
• Hemoglobin ≤14.5 g/dL,
• Leukocyte count >6x109/L,
• hsCRP ≥5 mg/L,
• Fecal calprotectin ≥300 µg/g,
• CDEIS>0
• infliximab trough
≥2 mg/L
Proportion Without Relapse
1.0
No. deleterious
factors
<4
0.8
4
0.6
0.4
5-6
0.2
>6
0.0
0
6
12
18
24
30
Months since infliximab withdrawal
Louis E et al. Gastroenterology. 2012;142:63-70.
A proSpective randomized controlled trial comParing
infliximAb-antimetabolites combination therapy to antimetabolites monotheRapy and infliximab monothErapy in
patients with Crohn’s disease in sustained steroid-free
remission on combination therapy
SPARE
Nycibdc
CCFA
Screening
Randomisation
Relapse
Continuing the combination
therapy at the same dosage
Judged as failure per protocol.
Managment at the discretion of
the investigator
Intensification of infliximab at
10 mg/Kg/8 weeks
If further relapse beyond one
year, the same treatment
regimen is applied
Discontinuing infliximab and
continuing the anti-metabolite
at the same dosage
Judged as failure per protocol.
Managment at the discretion of
the investigator
If further relapse within 1
year, the same retreatment
regimen is applied and a
scheduled treatment with 5
mg/Kg or 10 mg/Kg depending
how the remission was
recovered, is applied like in
group one
Discontinuing anti-metabolites
and continuing infliximab at the
same dosage
Scheduled
visits -3
Study end
infliximab 5 mg/Kg infusion. If
no remission at 4 weeks,
reinfusion at 10 mg/Kg
Crohn’s disease patients in
steroid-free remission for 6
months and treated with
infliximab and antimetabolites combination
therapy for at least 1 year,
infliximab being given at 5
mg/Kg /8 weeks for at least 6
months
Colonoscopy
Small bowel MRI
No remission
Infliximab intensification like in
first arm. If no remission, antimetabolite is restarted
Judged as failure per protocol.
Managment at the discretion of
the investigator
*
*
0
8
16
24
32
40
48
56
Timeline (weeks)
64
72
80
88
96
104
Comparative effectiveness research in IBD
A huge opportunity
Formidable challenges
• design
• recruitment
• funding
•…